DESCRIPTION Abstract Regenerative medicine holds immense promise for treating damaged and diseased tissues. One way to achieve this goal is to identify tissue-specific stem cells, which when introduced into organs, will stimulate regeneration. Alternatively, identification of triggers that stimulate tissue-specific progenitor cells will lead to development of small molecules or biologics to enhance the endogenous programs of tissue regeneration. Although experimental support exists for both therapeutic strategies, the molecular signals that trigger regenerative processes remain largely unknown. Although activation of the immune system, a universal response to injury, is a good candidate for triggering the tissue regeneration, the molecular pathways that directly link the immune system to progenitor cell biology remain poorly understood. We hypothesize that the ability of macrophages to penetrate tissue sites, integrate environmental inputs and transmit regenerative signals ideally positions these cells to be the central orchestrators of the regenerative response. In this model, recruited macrophages would form a mobile niche for tissue-specific progenitor cells, performing pleiotropic functions via enactment of distinct activation programs in spatially- and temporally-defined manner. Consistent with this view, our preliminary data show that deployment and activation of macrophages is essential for coordinating tissue regeneration after injury, including clearance of debris, activation and proliferation of tissue-specific stem cells, and differentiation of committed progenitors. Thus, the NIH Director's Pioneer Award Program will allow me to test the universality of these findings and to delineate molecular pathways for stimulating the endogenous programs of tissue regeneration, studies which collectively will be transformative for the field of regenerative medicine. Public Health Relevance Macrophages, the sentinels of host defense, are also the first cells to be recruited to site